Structure-conformation-activity relationships of renin inhibitory peptides having P1-P1' Xaaψ[CH2NH]Yaa substitutions: molecular modeling and crystallography studies1
✍ Scribed by Tomi K. Sawyer; Donald T. Pals; Boryeu Mao; Linda L. Maggiora; Douglas J. Staples; Anne E. deVaux; Heinrich J. Schostarez; John H. Kinner; Clark W. Smith
- Book ID
- 104203718
- Publisher
- Elsevier Science
- Year
- 1988
- Tongue
- French
- Weight
- 991 KB
- Volume
- 44
- Category
- Article
- ISSN
- 0040-4020
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✦ Synopsis
Structure-activity studres of angiotensinogen (ANG)-based renin mhtbitors having carboxyterminal pseudodipeptrdyl PI-PI' Xaa$(CH2NH]Yaa-NH2 and related transitron state synthetic mimetics were performed and integrated with molecular modeling using a computer simulated human renm active site model, and compared to a known crystallographic structure of a PI-PI' Phey(CH2NHlPhe substituted renin inhibitor bound to rhlzopuspepsin. Renin is an aspartic acid protease (EC 3.4.99.19) which catalyzes the first and rate-limiting step of the enzyme cascade that exists for the biosynthesis of angiotensin II (ANG lQ2-4. Renin inhibition may be therapeutically important in the development of useful antihypertensive agent&g based on the role of the renm-angiotensin converting enzyme cascade in the physiological and, perhaps, pathophysiological control of blood pressure and electrolyte homeostasis. In retrospect, the development of ANG-based inhibitors of human renm has essentially focused on systematic structure-activity studiesla-20 related to PI-PI' pseudodipeptidyl substitutions of the Leu-Val cleavage site (see below) of various substrate fragments in which the scissile amide (CONH) has been replaced by CH(OH)CHl or CH2NH type transition state mimics of the proposed amino1 (C(OH)zNH) that is believed to be generated during enzyme-catalyzed hydrolysis of ANG at the renin active site. 'Dedicated toThe Upjohn Company In honorofits 100th anmversary, 1886-1986